Use of PET Imaging to Assess the Efficacy of Thiethylperazine to Stimulate Cerebral MRP1 Transport Activity in Wild-Type and APP/PS1-21 Mice
Multidrug resistance-associated protein 1 (MRP1, encoded by the <i>ABCC1</i> gene) may contribute to the clearance of amyloid-beta (Aβ) peptides from the brain into the blood and stimulation of MRP1 transport activity may be a therapeutic approach to enhance brain Aβ clearance. In this s...
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| Format: | Article |
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MDPI AG
2022-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/12/6514 |
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| author | Michael Wölfl-Duchek Severin Mairinger Irene Hernández-Lozano Thomas Filip Viktoria Zoufal Mathilde Löbsch Johann Stanek Claudia Kuntner Thomas Wanek Martin Bauer Jens Pahnke Oliver Langer |
| author_facet | Michael Wölfl-Duchek Severin Mairinger Irene Hernández-Lozano Thomas Filip Viktoria Zoufal Mathilde Löbsch Johann Stanek Claudia Kuntner Thomas Wanek Martin Bauer Jens Pahnke Oliver Langer |
| author_sort | Michael Wölfl-Duchek |
| collection | DOAJ |
| description | Multidrug resistance-associated protein 1 (MRP1, encoded by the <i>ABCC1</i> gene) may contribute to the clearance of amyloid-beta (Aβ) peptides from the brain into the blood and stimulation of MRP1 transport activity may be a therapeutic approach to enhance brain Aβ clearance. In this study, we assessed the effect of thiethylperazine, an antiemetic drug which was shown to stimulate MRP1 activity in vitro and to decrease Aβ load in a rapid β-amyloidosis mouse model (APP/PS1-21), on MRP1 transport activity by means of positron emission tomography (PET) imaging with the MRP1 tracer 6-bromo-7-[<sup>11</sup>C]methylpurine. Groups of wild-type, APP/PS1-21 and <i>Abcc1<sup>(−/−)</sup></i> mice underwent PET scans before and after a 5-day oral treatment period with thiethylperazine (15 mg/kg, once daily). The elimination rate constant of radioactivity (<i>k</i><sub>elim</sub>) was calculated from time–activity curves in the brain and the lungs as a measure of tissue MRP1 activity. Treatment with thiethylperazine had no significant effect on MRP1 activity in the brain and the lungs of wild-type and APP/PS1-21 mice. This may either be related to a lack of an MRP1-stimulating effect of thiethylperazine in vivo or to other factors, such as substrate-dependent MRP1 stimulation, insufficient target tissue exposure to thiethylperazine or limited sensitivity of the PET tracer to measure MRP1 stimulation. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:34:53Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-345b7ceb1d814b2b93ff0baa533e5ae72023-11-23T17:02:06ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012312651410.3390/ijms23126514Use of PET Imaging to Assess the Efficacy of Thiethylperazine to Stimulate Cerebral MRP1 Transport Activity in Wild-Type and APP/PS1-21 MiceMichael Wölfl-Duchek0Severin Mairinger1Irene Hernández-Lozano2Thomas Filip3Viktoria Zoufal4Mathilde Löbsch5Johann Stanek6Claudia Kuntner7Thomas Wanek8Martin Bauer9Jens Pahnke10Oliver Langer11Department of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, AustriaPreclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, 2444 Seibersdorf, AustriaPreclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, 2444 Seibersdorf, AustriaPreclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, 2444 Seibersdorf, AustriaDepartment of Biomedical Imaging und Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Biomedical Imaging und Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Biomedical Imaging und Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Neuro-/Pathology, Oslo University Hospital (OUS), University of Oslo (UiO), 0424 Oslo, NorwayDepartment of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, AustriaMultidrug resistance-associated protein 1 (MRP1, encoded by the <i>ABCC1</i> gene) may contribute to the clearance of amyloid-beta (Aβ) peptides from the brain into the blood and stimulation of MRP1 transport activity may be a therapeutic approach to enhance brain Aβ clearance. In this study, we assessed the effect of thiethylperazine, an antiemetic drug which was shown to stimulate MRP1 activity in vitro and to decrease Aβ load in a rapid β-amyloidosis mouse model (APP/PS1-21), on MRP1 transport activity by means of positron emission tomography (PET) imaging with the MRP1 tracer 6-bromo-7-[<sup>11</sup>C]methylpurine. Groups of wild-type, APP/PS1-21 and <i>Abcc1<sup>(−/−)</sup></i> mice underwent PET scans before and after a 5-day oral treatment period with thiethylperazine (15 mg/kg, once daily). The elimination rate constant of radioactivity (<i>k</i><sub>elim</sub>) was calculated from time–activity curves in the brain and the lungs as a measure of tissue MRP1 activity. Treatment with thiethylperazine had no significant effect on MRP1 activity in the brain and the lungs of wild-type and APP/PS1-21 mice. This may either be related to a lack of an MRP1-stimulating effect of thiethylperazine in vivo or to other factors, such as substrate-dependent MRP1 stimulation, insufficient target tissue exposure to thiethylperazine or limited sensitivity of the PET tracer to measure MRP1 stimulation.https://www.mdpi.com/1422-0067/23/12/6514MRP1 stimulationPETbrainAlzheimer’s diseaseamyloid-betathiethylperazine |
| spellingShingle | Michael Wölfl-Duchek Severin Mairinger Irene Hernández-Lozano Thomas Filip Viktoria Zoufal Mathilde Löbsch Johann Stanek Claudia Kuntner Thomas Wanek Martin Bauer Jens Pahnke Oliver Langer Use of PET Imaging to Assess the Efficacy of Thiethylperazine to Stimulate Cerebral MRP1 Transport Activity in Wild-Type and APP/PS1-21 Mice International Journal of Molecular Sciences MRP1 stimulation PET brain Alzheimer’s disease amyloid-beta thiethylperazine |
| title | Use of PET Imaging to Assess the Efficacy of Thiethylperazine to Stimulate Cerebral MRP1 Transport Activity in Wild-Type and APP/PS1-21 Mice |
| title_full | Use of PET Imaging to Assess the Efficacy of Thiethylperazine to Stimulate Cerebral MRP1 Transport Activity in Wild-Type and APP/PS1-21 Mice |
| title_fullStr | Use of PET Imaging to Assess the Efficacy of Thiethylperazine to Stimulate Cerebral MRP1 Transport Activity in Wild-Type and APP/PS1-21 Mice |
| title_full_unstemmed | Use of PET Imaging to Assess the Efficacy of Thiethylperazine to Stimulate Cerebral MRP1 Transport Activity in Wild-Type and APP/PS1-21 Mice |
| title_short | Use of PET Imaging to Assess the Efficacy of Thiethylperazine to Stimulate Cerebral MRP1 Transport Activity in Wild-Type and APP/PS1-21 Mice |
| title_sort | use of pet imaging to assess the efficacy of thiethylperazine to stimulate cerebral mrp1 transport activity in wild type and app ps1 21 mice |
| topic | MRP1 stimulation PET brain Alzheimer’s disease amyloid-beta thiethylperazine |
| url | https://www.mdpi.com/1422-0067/23/12/6514 |
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